Temporal regulation of pulmonary inflammation by MyD88 alternative pre-mRNA splicing

摘要 在美国，急性肺部炎症疾病每年影响超过1亿人。急性 这些患者的炎症反应是对抗感染所必需的， 损害因此，适当解决炎症对患者康复至关重要。肺泡巨噬细胞 (AMs)作为炎症反应的关键协调者，在启动和消退中发挥作用 炎症。然而，AM用于指导炎症消退的机制是 不完全理解。此外，两种不同的AM亚群调节炎症。居民AM是 存在于整个生命的空气空间;他们作为第一反应的病原体，但其炎症 程序被迅速下调。募集的AM来自迁移到肺的循环单核细胞 在炎症过程中，这些细胞产生的炎症介质比常驻细胞产生的炎症介质更持久。 AM驱动这些AM群体对炎症的不同作用的机制仍有待进一步研究。 阐明。我们已经发现MyD 88的前体mRNA的选择性剪接，MyD 88是一种在细胞内起作用的信号衔接子， 多种Toll样受体和IL-1受体信号通路，在终止pro-IL-1的过程中起着关键作用。 AM中的炎性介质产生。因此，我们假设MyD 88的剪接改变提供了一个新的机制。 中枢制动AM促炎反应并用于限制持续性炎症。我们进一步 假设MyD 88选择性剪接的作用在不同的AM亚群中不同。为了验证这一 假设，我们将研究MyD 88选择性剪接的生理效应：（1）小鼠常驻AM 离体和体内，（2）小鼠离体和体内募集的AM，和（3）从患者分离的人AM 急性炎症性肺病这些研究将证明针对这一点的潜在效用。 调节机制，以治疗急性炎症性肺病患者。

ABSTRACT Acute inflammatory diseases of the lungs affect more than 100 million people in the U.S. annually. The acute inflammatory response in these patients is required to combat infection but also causes significant tissue damage. Thus, proper resolution of inflammation is critical for patient recovery. Lung airspace macrophages (AMs) serve as key orchestrators of the inflammatory response, functioning in both the initiation and resolution of inflammation. However, the mechanisms used by AMs to direct the resolution of inflammation are incompletely understood. Moreover, two different AM subsets modulate inflammation. Resident AMs are present in the airspaces throughout life; they serve as first responders to pathogens but their inflammatory programs are quickly down-regulated. Recruited AMs arise from circulating monocytes that migrate to the lung during inflammation; inflammatory mediator production by these cells is more persistent than that of resident AMs. The mechanisms that drive the divergent effects of these AM populations on inflammation remain to be elucidates. We have found that alternative pre-mRNA splicing of MyD88, a signaling adaptor that functions in multiple Toll-like receptor and IL-1 receptor signaling pathways, plays a key role in terminating pro- inflammatory mediator production in AMs. Thus we hypothesize that altered splicing of MyD88 provides a central brake on AM pro-inflammatory responses and serves to limit persistent inflammation. We further postulate that the role of MyD88 alternative splicing differs in different AM subpopulations. To test this hypothesis, we will investigate the physiological effect of alternative MyD88 splicing in: (1) mouse resident AMs ex vivo and in vivo, (2) mouse recruited AMs ex vivo and in vivo, and (3) human AMs isolated from patients with acute inflammatory lung disease. These studies will demonstrate the potential utility of targeting this regulatory mechanism to treat patients with acute inflammatory lung disease.